The objectives of this program are to characterize the immunosuppressive properties of a retroviral envelope protein (p15E) and to determine its role in retroviral disease. Earlier, we demonstrated that FeLV p15E suppressed lymphocyte blastogenesis and lymphocyte membrane mobility (receptor capping) of cat, human and dog peripheral blood lymphocytes (PBL). Recently, the protein was found to suppress the one-way mixed lymphocyte reaction and to inhibit proliferation of erythroid colony-forming cells but not granulocyte/macrophage colony-forming cells in vitro. Attempts to determine which specific cell types are affected have indicated that both B lymphocytes and macrophages are resistant, whereas T-cell functions appear sensitive. FeLV p15E did not interfere with B-cell immunoglobulin capping or macrophage production of interleukin-1, whereas it significantly affected Con A capping and interleukin-2 simulation, both T cell-dependent functions. The mechanism of the action of FeLV p15E is unknown; however, research with the prostaglandin and cyclic nucleotide systems has led to a possible answer. Using sensitive radioimmune precipitation assays to measure prostaglandin and cyclic nucleotide levels, we have found that prostaglandin synthesis (PGE2, PGI2, PGF2 and TXB2) was not affected by FeLV p15E, whereas cyclic nucleotide (cAMP) levels were altered. Specific inhibitors of prostaglandin synthesis, indomethacin and nordihydroguaiaretic acid, reversed the FeLV p15E-induced suppression of lymphocyte blastogenesis and capping. Neither inhibitor had any effect on normal lymphocyte capping or blastogenesis. Indomethacin also increased capping and blastogenesis of lymphocytes from FeLV-infected (immunosuppressed) cats. Using other specific inhibitors of prostaglandin synthesis, we found that inhibitors of thromboxane synthesis and prostacyclin synthesis had no augmenting capabilities. Research to date indicates that modulation of AMP levels by FeLV p15E may mediate its immunosuppressive effect. This effect may be of secondary importance, in that altered cAMP levels may reflect changes caused by FeLV p15E at the level of the cell membrane.